Applications of Propargyl Esters of Amino Acids in Solution-Phase Peptide Synthesis

Ramesh, Ramapanicker; Gupta, Roshmi; Rajendran, Megha; Chandrasekaran, Srinivasan

doi:10.1155/2011/854952

Cited by 6 publications

(7 citation statements)

References 9 publications

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“…Propargyl-functionalized phenylalanine (Phe-OPr) was prepared by the esterification of phenylalanine with propargyl alcohol using dry HCl. 42 Propargylated ionic liquid [PrMIM]Br was prepared from propargyl bromide and 1- methylimidazolium. The detailed synthetic strategies, purifications, and characterizations of different intermediates of the above-mentioned compounds and their final products were given in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

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Polymer-Assisted Chain-like Organization of CuNi Alloy Nanoparticles: Solvent-Adoptable Pseudohomogeneous Catalysts for Alkyne–Azide Click Reactions with Magnetic Recyclability

et al. 2014

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A solution-phase reduction method is undertaken to produce polymer magnetic bimetallic CuNi nanoalloy with chain-like structures, which are formed by the magnetic dipole-directed assembly of spherical alloy nanoparticles as confirmed from TEM analysis. Magnetic property measurement reveals paramagnetic nature of the alloy nanochain. These polymer-capped chain-like alloy nanoparticles are dispersible in water as well as in organic solvents that increase their ease of application as catalyst in both of these environments. The XPS and zeta potential analysis demonstrates the presence of Cu(I) on the alloy particle surface and justifies their catalytic activity toward alkyne–azide click reactions. Consequently, the catalytic activity of the as-synthesized polymer CuNi alloy nanochain is investigated toward a wide variety of alkyne–azide click reactions at room temperature in water and in DMF. Depending upon the nature of the substrate and the surface stabilizing polymer on the nanocatalyst, a moderate to quantitative yield of the click-conjugated product is obtained. Additionally, the advantage of pseudohomogeneity of CuNi nanoalloy suspension is utilized to modify polymer end group with amino acid and peptide with ionic liquid via click reaction to create new bioconjugates. Moreover, the nanoalloy catalyst is magnetically recoverable and reusable up to three cycles of click reactions without losing much of its original activity.

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Section: Methodsmentioning

confidence: 99%

“…Finally, Peptide-N 3 was obtained by reacting bromo-peptide with NaN 3 in DMF. Propargyl-functionalized phenylalanine (Phe-OPr) was prepared by the esterification of phenylalanine with propargyl alcohol using dry HCl . Propargylated ionic liquid [PrMIM]Br was prepared from propargyl bromide and 1-methylimidazolium.…”

Section: Methodsmentioning

confidence: 99%

Polymer-Assisted Chain-like Organization of CuNi Alloy Nanoparticles: Solvent-Adoptable Pseudohomogeneous Catalysts for Alkyne–Azide Click Reactions with Magnetic Recyclability

et al. 2014

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“…1 General procedure for the synthesis of azides (27)(28)(29)(30)(31)(32)(33)(34). Example: synthesis of N-(4-fluorobenzyl)-3-azidopropanamide (28) To a solution of 3-bromopropionic acid, 25 (19.61 mmol, 3.0 g) in anhyd. DMF (10 mL) was added sodium azide (39.22 mmol, 2.55 g).…”

Section: Chemistrymentioning

confidence: 99%

Effect of novel triazole–amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies

et al. 2016

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The increasing incidence of human candidiasis and the tendency of Candida species to become resistant to existing chemotherapies are well-recognized health problems. The present study demonstrates the successful synthesis of novel triazole-amino acid hybrids with potent in vitro and in vivo inhibitory activity against Candida species. Particularly, compounds 68 and 70 showed potent in vitro activity against fluconazole (FLC) resistant as well as sensitive clinical isolates of Candida albicans. Time kill curve analysis of lead inhibitors 68 and 70 showed their fungistatic nature. Secretion of hydrolytic enzymes, mainly proteinases and phospholipases, decreased considerably in the presence of 68 and 70 indicating their interference in fungal virulence. TEM analysis of Candida cells exposed to compounds 68 and 70 clearly showed morphological changes and intracellular damage as their possible mode of action. A preliminary mechanistic study carried out on the two most effective inhibitors (68 and 70) revealed the inhibition of ergosterol biosynthesis thereby causing the cells to lose their integrity and viability. The selected compounds did not show significant cytotoxicity up to a concentration of 200 μg mL in the HEK293 cell line. An in silico analysis of 68 and 70 binding to a modeled C. albicans CYP51 showed critical H-bonding as well as hydrophobic interactions with the important active site residues indicating the basis of their anti-Candida role. Studies on the larvae of Galleria mellonella showed that the selected inhibitors (68 and 70) were non-toxic, did not provoke an immune response and significantly reduced Candida proliferation in vivo.

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“…The formation of a black by-product was thought to be due to a side reaction with acetyl chloride resulting in polymerisation of the propargyl alcohol. Accordingly, an alternative method reported by Ramapanicker and colleagues 108 was then employed in which they state that no black by-product formed. Their methodology involves first bubbling HCl gas through cold propargyl alcohol to provide a saturated HCl solution before the addition of glycine.…”

Section: CLmentioning

confidence: 99%

“…Scheme 2.14: Unsuccessful syntheses of propargyl glycinate hydrochloride utilising methodology proposed by both Patnaik and colleagues 93 and Ramapanicker and colleagues. 108 Due to the unsuccessful synthesis of propargyl glycinate hydrochloride, a new synthetic strategy for propargyl diazoacetate that by-passed the propargyl glycinate hydrochloride altogether was required. A method first reported by Fukuyama and colleagues 109 was selected due to its high yielding synthesis of propargyl diazoacetate and its reduced explosive characteristics.…”

Section: Calculated Coupling Constantsmentioning

confidence: 99%

Identifying the Mechanism of Action of Bioactive 1,2-Cyclopropyl Carbohydrates

Lassueur¹

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<p>Cyclopropanes and carbohydrates have long been used in the field of drug development. Previous work has shown that 1,2-cyclopropyl carbohydrates display bioactivity in both HeLa cancer cell lines¹ and in yeast² with a tentatively proposed mechanism of inhibition occurring through an enzymatic cyclopropane ring opening reaction and subsequent formation of a covalent bond with a target enzyme.² A small library of 1,2-cyclopropyl carbohydrate derivatives were synthesised based on known pharmacophores to examine further the potential mechanism of inhibition of such compounds and confirm the occurrence of enzyme-catalysed cyclopropane ring-opening reactions. Initial synthetic efforts were focused on the synthesis of the 1,2-dichlorocyclopropyl carbohydrate 23, which, through the optimisation of an essential C-6 detritylation reaction, was achieved in moderate yields of 32% over 7 steps. Following this, the ethoxycarbonyl substituted 1,2-cyclopropyl carbohydrate 54 was synthesised over 7 steps in a 22% yield through a rhodium acetate-catalysed addition of ethyl diazoacetate (49) to the glucal substrate 40. It was envisioned that if enzymatic cyclopropane ring-opening was occurring to form a C-7 carbanion, this would in turn be stabilised through the potential enolate formation of 54. Use of N,N-ditosylhydrazine in the synthesis of propargyl diazoacetate (58) followed by a rhodium acetate-catalysed cyclopropanation of 58 with substrate 40 resulted in the successful synthesis of 61 over 7 steps in a total yield of 9%. The incorporation of the propargyl substituent in 61 was introduced as a molecular probe in an attempt to isolate the target protein through an affinity purification procedure. The bioactivity of the propargyl derivative 61 was consistent with the synthesised compounds 23 and 54. It was proposed that these compounds undergo an enzymatic cyclopropane ring opening reaction accompanied with a clear diastereoselective preference for the α-stereoisomer of the cyclopropane ring, consistent with a target-based activation of the compounds. Chemical genetic analysis of the resulting bioactive compounds was undertaken using a deletion mutant array of Saccharomyces cerevisiae to elucidate a potential mechanism of action. Analysis of the results showed that, of the 4800 homozygous deletion strains tested in the high-throughput screens, a total of 122 strains were found following validation to sensitise and 68 to give resistance against 23 and 54. These sensitive and resistant mutants were subjected to a validation assay. Following validation, genes whose deletion led to sensitivity or resistance were then subjected to gene ontology term enrichment analysis which showed enrichment in the cytosolic ribosome, SNARE complex and SNAP receptor activity for resistant strains and enrichment in endoplasmic reticulum and endomembrane systems was found for the sensitive strain. Genes whose deletion sensitised to both compounds showed strong enrichment in cellular protein localisation, intra-golgi vesicale-mediated transport and the endomembrane system. Target identification and isolation were attempted through an affinity purification procedure using compound 61 and an azide-modified agarose resin. However, this was without success, either through inaccessibility of the alkyne of the target probe or because the target resides in the membrane-associated fraction which was discarded prior to treatment with the probe. This study suggests that the 1,2-cyclopropyl carbohydrates synthesised function through a cyclopropane ring-opening reaction, assisted by an enzymatic nucleophile. Chemical genetic analysis showed that the target of these compounds is involved in protein transport and protein localisation most likely relating to the vesicle tethering. Although many aspects of this work still need further investigation, either through the synthesis of new 1,2-cyclopropyl carbohydrates to increase bioactivity and better understand the enzymatic target, or through further biological procedures to better understand the mechanism of action, the use of 1,2-cyclopropyl carbohydrates as a potential pharmaceuticals or probes of protein trafficking shows much promise.</p>

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Applications of Propargyl Esters of Amino Acids in Solution-Phase Peptide Synthesis

Cited by 6 publications

References 9 publications

Polymer-Assisted Chain-like Organization of CuNi Alloy Nanoparticles: Solvent-Adoptable Pseudohomogeneous Catalysts for Alkyne–Azide Click Reactions with Magnetic Recyclability

Polymer-Assisted Chain-like Organization of CuNi Alloy Nanoparticles: Solvent-Adoptable Pseudohomogeneous Catalysts for Alkyne–Azide Click Reactions with Magnetic Recyclability

Effect of novel triazole–amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies

Identifying the Mechanism of Action of Bioactive 1,2-Cyclopropyl Carbohydrates

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